The neutral amino acid, 4-aminobutanoic acid (GABA), is an inhibitory transmitter in the central nervous system. There is considerable direct and indirect evidence that impaired operation of GABA-mediated inhibitory synapses may be an important causative factor in seizure disorders (P. Krogsgaard-Larsen et al., Epilepsy Res. 1987, 1, 77-93) making GABA-ergic drugs potential antiepileptic therapeutic agents.
Furthermore, enhancement of GABA-ergic activity may be useful in the treatment of anxiety, pain, muscular and movement disorders and mental and emotional disorders (W. Loscher, Eur. J. Pharmacol., 1985, 110, 103-108).
While direct stimulation of GABA receptors by agonists does not seem to represent the most suitable therapeutic approach to epileptic diseases (R. G. Fariello et al., Eds., Neutransmitters, Seizures, and Epilepsy II, 1984, New York, Raven Press; B. Meldrum and R. Horton, Eur. J. Pharmacol. 1980, 61, 231-237; Krogsgaard-Larsen et al., J. Med. Chem. 1994, 37, 2489-2505.), GABA neurotransmission may be facilitated by manipulation of the GABA uptake mechanisms. Pharmacological inhibition of the neuronal and/or glial GABA transport, assumed to be responsible for the termination of GABA neurotransmission processes, provides a mechanism for sustaining levels of synaptically released GABA in the synapses and thereby increasing GABA-mediated transmission (P. Krogsgaard-Larsen et al., J. Med. Chem. 1994, 37, 2489-2505).
The strategies for such pharmacological interventions may be: 1) effective blockade of both neuronal and glial GABA uptake, or 2) selective blockade of the uptake of GABA into glial cells in order to increase the amount of GABA taken up by the neuronal carrier with subsequent elevation of the GABA concentration in nerve terminals. There is evidence suggesting that glia-selective GABA uptake inhibitors may have particular interest as antiepileptic agents (E. Falch et al., Drug Design and Delivery, 1987, 2, 9-21; Falch et al. Drug Dev. Res., 1990, 21, 169-188).
Classical GABA uptake inhibitors are nipecotic acid, guvacine and THPO. Oral active N-substituted derivatives of nipecotic acid and guvacine are described in F. E. Ali et al., J. Med. Chem. 1985, 28, 553-560; U.S. Pat. No. 4,383,999 and U.S. Pat. No. 4,514,414 to SmithKline Beckmann Corporation; EP 236342 and EP 231996 to Novo Industri A/S and H. S. White et al., Eur. J. Pharmacol. 1993, 236, 147-149.
With regard to convulsion, especially epilepsy, in spite of the fact that antiepileptic drugs are available, many patients fail to experience seizure control. Consequently, it is an object of the present invention to provide new GABA'ergic drugs effective in the treatment of diseases associated with GABA neurotransmission, in particular seizure control.